MK-0731 - CAS 845256-65-7
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Not Intended for Therapeutic Use. For research use only.
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MK-0731 is a synthetic small molecule with potential antineoplastic activity. MK0731 selectively inhibits kinesin spindle protein (KSP), which may result in the inhibition of mitotic spindle assembly, induction of cell cycle arrest during the mitotic phase, and apoptosis in tumor cells that overexpress KSP.
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B0084-137625 5 mg $799 In stock
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Brife Description:
potential antineoplastic agent, inhibitor of kinesin spindle protein (KSP)
ALR-3456; 845256-65-7; MK 0731; UNII-8HIJ5G3O02; 8HIJ5G3O02
potential antineoplastic agent
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1.Discovery of novel spiro 1,3,4-thiadiazolines as potent, orally bioavailable and brain penetrant KSP inhibitors.
Mansoor UF1, Angeles AR2, Dai C2, Yang L2, Vitharana D2, Basso AD3, Gray K3, Tang H4, Liu M3, Liang L3, Allbritton O3, Siddiqui MA2. Bioorg Med Chem. 2015 May 15;23(10):2424-34. doi: 10.1016/j.bmc.2015.03.052. Epub 2015 Mar 27.
Kinesin spindle protein (KSP) is a mitotic kinesin that is expressed only in proliferating cells and plays a key role in spindle pole separation, formation of a bipolar mitotic spindle, as well as centrosome separation and maturation. Inhibition of KSP has the potential to provide anti-tumor activity while avoiding peripheral neuropathy associated with some microtubule-targeted drugs. Based on MK-0731 and related heterocyclic compounds targeting the KSP monastrol binding site, structurally constrained spiro-cyclic KSP inhibitors were designed. In particular, rapid evaluation and optimization of the novel spiro 1,3,4-thiadiazolines resulted in a series of potent KSP inhibitors demonstrating mechanism based activities in cells, including induction of the mitotic marker phospho-histone H3 and induction of monaster spindle formation. Further optimization of the pharmacokinetic (PK) properties afforded MK-8267 as a potent, orally bioavailable and brain penetrant KSP inhibitor which showed anti-tumor activity in preclinical xenograft models.
2.Kinesin spindle protein (KSP) inhibitors. 9. Discovery of (2S)-4-(2,5-difluorophenyl)-n-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (M
Cox CD1, Coleman PJ, Breslin MJ, Whitman DB, Garbaccio RM, Fraley ME, Buser CA, Walsh ES, Hamilton K, Schaber MD, Lobell RB, Tao W, Davide JP, Diehl RE, Abrams MT, South VJ, Huber HE, Torrent M, Prueksaritanont T, Li C, Slaughter DE, Mahan E, Fernandez-Me J Med Chem. 2008 Jul 24;51(14):4239-52. doi: 10.1021/jm800386y. Epub 2008 Jun 25.
Inhibition of kinesin spindle protein (KSP) is a novel mechanism for treatment of cancer with the potential to overcome limitations associated with currently employed cytotoxic agents. Herein, we describe a C2-hydroxymethyl dihydropyrrole KSP inhibitor ( 11) that circumvents hERG channel binding and poor in vivo potency, issues that limited earlier compounds from our program. However, introduction of the C2-hydroxymethyl group caused 11 to be a substrate for cellular efflux by P-glycoprotein (Pgp). Utilizing knowledge garnered from previous KSP inhibitors, we found that beta-fluorination modulated the p K a of the piperidine nitrogen and reduced Pgp efflux, but the resulting compound ( 14) generated a toxic metabolite in vivo. Incorporation of fluorine in a strategic, metabolically benign position by synthesis of an N-methyl-3-fluoro-4-(aminomethyl)piperidine urea led to compound 30 that has an optimal in vitro and metabolic profile. Compound 30 (MK-0731) was recently studied in a phase I clinical trial in patients with taxane-refractory solid tumors.
3.A phase I trial of MK-0731, a kinesin spindle protein (KSP) inhibitor, in patients with solid tumors.
Holen K1, DiPaola R, Liu G, Tan AR, Wilding G, Hsu K, Agrawal N, Chen C, Xue L, Rosenberg E, Stein M. Invest New Drugs. 2012 Jun;30(3):1088-95. doi: 10.1007/s10637-011-9653-1. Epub 2011 Mar 22.
PURPOSE: The kinesin spindle protein (KSP) is essential for separation of spindle poles during mitosis. Its inhibition results in mitotic arrest. This phase I trial examined safety, tolerability, dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetic parameters, and anti-tumor activity of MK-0731, a potent inhibitor of KSP.
4.Discovery of allosteric inhibitors of kinesin spindle protein (KSP) for the treatment of taxane-refractory cancer: MK-0731 and analogs.
Cox CD1, Garbaccio RM. Anticancer Agents Med Chem. 2010 Nov 1;10(9):697-712.
Current cancer chemotherapy relies heavily on cytotoxic agents, such as the taxanes and Vinca alkaloids, that interfere with the cellular machinery required for cell division and divert the cell down a pathway of programmed cell death. These antimitotic agents, or spindle poisons, target the mitotic spindle by binding to tubulin, a protein required not only for mitosis but also for structural integrity and proper function of healthy, terminally differentiated cells. To avoid side effects attributed to this nonselective mechanism of action, new targets in the mitotic pathway that act only in dividing cells were sought and a leading candidate to emerge from these efforts was kinesin spindle protein (KSP or HsEg5). KSP is a molecular motor protein that is expressed only during mitosis and controls the formation of a functional mitotic spindle. Inhibition of KSP causes mitotic arrest followed by cell death in malignant cells and thus has the potential to become a novel chemotherapeutic strategy with the potential for reduced toxicity.
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